Polycyclic aromatic hydrocarbons (PAH) are a class of environmental chemicals that are known to cause toxicity and cancers in humans. The molecular changes induced by exposure to PAH are mediated by the aryl hydrocarbon receptor (AHR). In particular, the AHR mediates up-regulation of phase I and phase II xenobiotic metabolizing enzymes that can cause both bioactivation and detoxification of PAH. Indeed, there is a fine balance between bioactivation and detoxification of chemical carcinogens that are directly influenced by AHR-dependent signaling. Emerging evidence indicates that PPAR?/? may modulate AHR activity in skin/keratinocytes, and that this interaction will significantly alter the balance between bioactivation and detoxification leading to differences in the susceptibility to chemically-induced toxicity. For Specific Aim 1, we will determine the mechanisms by which PPAR?/? can modulate AHR activity with an emphasis on receptor heterodimer translocation and critical transcriptional events necessary for increasing expression of xenobiotic metabolism that are necessary for bioactivation and detoxification of PAH. For Specific Aim 2, we will determine if PPAR?/? can functionally alter PAH-induced skin carcinogenesis mediated by AHR. Results from these studies will elucidate novel regulatory mechanisms of AHR-dependent signaling that are central in mediating the toxic and carcinogenic effects caused by exposure to environmental PAH. Importantly, results from these studies might help explain the significant variation in AHR-dependent function in humans, since no functional polymorphisms in the Ahr have been identified. PUBLIC HEALTH RELEVANCE: Exposure to environmental chemicals such as polycyclic aromatic hydrocarbons can cause toxicity and cancers in humans, with associated costs exceeding $100 billion annually. The causes of chemically-induced toxicity and cancer are very unclear. Thus, it is essential to determine the mechanisms underlying chemically-induced toxicity and carcinogenesis. While it is well accepted that the aryl hydrocarbon receptor is required to mediate cellular changes that can both cause (bioactivation) and prevent (detoxification), emerging evidence suggests that other proteins may also affect AHR activity. In these studies, we will examine new proteins that may interact with AHR signaling and identify novel pathways that may modulate chemically- induced toxicity and cancers.